Drug Delivery Device

ABSTRACT

The disclosure relates to a drug delivery device for expelling a pre-determined or pre-settable amount of a liquid medicament formulation which improves the stalling behavior and indicates the stalling state to the user. The device comprises: 
     a medicament reservoir attached to a housing and 
     an expelling mechanism configured for acting against the medicament reservoir in order to expel a portion of the liquid medicament formulation therefrom, the expelling mechanism comprising
         an arrangement of a threaded nut in a fixed axial relation to the housing and a lead screw in threaded engagement with the threaded nut, the threaded nut and the lead screw being rotatable relative to each other by a rotational input interface,   a mechanical energy reservoir (for storing energy, the stored energy being releasable from the energy reservoir by a rotational interface,   a drive train having upstream and downstream interfaces; and   a trigger movable relative to the housing.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is the national stage entry of InternationalPatent Application No. PCT/EP2018/074693, filed on Sep. 13, 2018, andclaims priority to Application No. EP 17306191.2, filed on Sep. 15,2017, the disclosures of which are incorporated herein by reference.

TECHNICAL FIELD

The disclosure relates to a drug delivery device for selecting anddispensing a number of user variable doses of a medicament.

BACKGROUND

Pen type drug delivery devices have application where regular injectionby persons without formal medical training occurs. This may beincreasingly common among patients having diabetes where self-treatmentenables such patients to conduct effective management of their disease.In practice, such a drug delivery device allows a user to individuallyselect and dispense a number of user variable doses of a medicament.

There are basically two types of drug delivery devices: resettabledevices (i.e., reusable) and non-resettable (i.e., disposable). Forexample, disposable pen delivery devices are supplied as self-containeddevices. Such self-contained devices do not have removable pre-filledcartridges. Rather, the pre-filled cartridges may not be removed andreplaced from these devices without destroying the device itself.Consequently, such disposable devices need not have a resettable dosesetting mechanism. The present disclosure may be applicable for bothtypes of devices, i.e. for disposable devices as well as for reusabledevices.

These types of pen delivery devices (so named because they oftenresemble an enlarged fountain pen) generally comprise three primaryelements: a cartridge section that includes a cartridge often containedwithin a housing or holder; a needle assembly connected to one end ofthe cartridge section; and a dosing section connected to the other endof the cartridge section. A cartridge (often referred to as an ampoule)typically includes a reservoir that is filled with a medication (e.g.,insulin), a movable rubber type bung or stopper located at one end ofthe cartridge reservoir, and a top having a pierceable rubber seallocated at the other, often necked-down, end. A crimped annular metalband is typically used to hold the rubber seal in place. While thecartridge housing may be typically made of plastic, cartridge reservoirshave historically been made of glass.

The needle assembly is typically a replaceable double-ended needleassembly. Before an injection, a replaceable double-ended needleassembly is attached to one end of the cartridge assembly, a dose isset, and then the set dose is administered. Such removable needleassemblies may be threaded onto, or pushed (i.e., snapped) onto thepierceable seal end of the cartridge assembly.

The dosing section or dose setting mechanism is typically the portion ofthe pen device that is used to set (select) a dose. During an injection,a spindle or lead screw contained within the dose setting mechanismpresses against the bung or stopper of the cartridge. This force causesthe medication contained within the cartridge to be injected through anattached needle assembly. After an injection, as generally recommendedby most drug delivery device and/or needle assembly manufacturers andsuppliers, the needle assembly is removed and discarded.

A further differentiation of drug delivery device types refers to thedrive mechanism: There are devices which are manually driven, e.g. by auser applying a force to an injection button (trigger), devices whichare driven by a spring or the like and devices which combine these twoconcepts, i.e. spring assisted devices which still require a user toexert an injection force. The spring-type devices involve springs whichare preloaded and springs which are loaded by the user during doseselecting. Some stored-energy devices use a combination of springpreload and additional energy provided by the user, for example duringdose setting.

The spring assisted devices often use a preloaded and/or user-loadedtorsion spring (drive spring) in order to provide the necessary force(i.e. a torque) to drive the drive mechanism for dispensing themedicament dose. In this type of drug delivery devices the torque of thedrive spring is transferred to the drive train of the drive mechanismand via the drive train which transfers the torque into a linearmovement driving the bung of the cartridge for medicament dispensingfrom the cartridge through a needle connected to the cartridge. Duringnormal conditions the full amount of torque provided by the drive springis released as medicament fluid continues to be dispensed from theneedle until the device reaches an equilibrium state which is a lowstress state.

However, under certain circumstances, for example, if the needle isblocked, stalling occurs. Stalling is when a mechanism cannot fullyrelieve the mechanical energy stored in the wind-up system and ininternal drive train strain within the predetermined time period ofrelease button actuation for injection, which means injection time andholding time after injection (e.g. 30 seconds). There are two differenttypes of stalling behaviour, namely obvious stalling and hiddenstalling. The stalling is called obvious stalling if the drive mechanismstops before producing feedback indicative for correct completion ofinjection, whereas hidden stalling is defined such that the drivemechanism produces feedback indicative for completion of injectionwithout fully relieving internal strain and hence without fullydispensing the dose. If, for example, users are instructed by theinformation for use to observe the entire return of the dose dialdisplay to the “0” marking in order to correctly determine the end ofthe expelling operation, a hidden stalling condition may occur when themechanism remains in a strained state exactly at that point. The effectof the strain is a backlash in the parts of the drive train that aredownstream relative to the dose dial display. The extent of the backlashclearly corresponds to the elasticity of the strained drive trainportion and, especially for small doses, may result in a considerableunderdose. Root causes of stalling are not limited to the injectiondevice itself and thereby cannot be exhaustively addressed by meremechanism improvements. For example, stalling may occur as the result ofneedle bending by inadequate handling of the device. As stalling cannotbe avoided in all circumstances the mechanical layout of the devicetherefore should be at least such that any stalling conditions willbecome apparent to a normally attentive user. This ability of aninjection device shall be denoted as a well-defined stalling behaviour.

In one example the torque from the drive spring is transferred from adrive sleeve to a lead screw (e.g. via corresponding spline features)and then to the body of the drug delivery device, where it is convertedto a linear axial motion via a thread contact. The axial movement of thelead screw causes the bung of the cartridge to move and dispense fluidfrom the needle. In a normal dispense with a working needle, when thedevice reaches the 0 units stop, no further energy is released from thedrive spring. The residual torsion due to deflection of the drivemechanism components is then released as fluid continues to be dispensedfrom the needle, until the device reaches the above mentionedequilibrium state. When the needle is blocked the torsion in the drivemechanism cannot be released because the lead screw cannot advance.

SUMMARY

An object of the present disclosure may be seen in providing an improveddrug delivery device with regard to its stalling behaviour. Especially,it may be understood as an object of the present disclosure to provide adrug delivery device which indicates its state with regard to stallingto the user.

This object is solved by a drug delivery device according to claim 1.

In general, a drug delivery device for automatically expelling apre-determined or pre-settable amount of a liquid medicament formulationis provided,

the device comprising

a medicament reservoir attached to a housing and

an expelling mechanism configured for linearly acting against themedicament reservoir (e.g. its bung) in order to expel a portion of theliquid drug formulation therefrom, the expelling mechanism comprising

-   -   an arrangement of a threaded nut in a fixed axial relation to        the housing and a lead screw in threaded engagement with the        threaded nut, the threaded nut and the lead screw being        rotatable relative to each other by a rotational input        interface,    -   a mechanical energy reservoir for storing energy, the stored        energy being releasable from the energy reservoir by a        rotational interface, for example for providing a driving torque        and transferring the driving torque to the lead screw for        rotation and axial movement relative to the housing,    -   a drive train, in one embodiment comprising a drive sleeve,        having an upstream interface coupled to the rotational interface        of the energy reservoir for feeding rotational energy into the        drive train and a downstream interface coupled to the rotational        input interface of the arrangement of the threaded nut and the        lead screw for outputting rotational energy thereto to thereby        rotate the lead screw and the threaded nut relative to each        other, the drive train further being equipped with a releasable        latch for preventing (i.e. in an initial position) transfer of        rotational energy from the upstream interface to the downstream        interface when actuated and for allowing transfer of rotational        energy from the upstream interface to the downstream interface        when released; and    -   a trigger, e.g. a button, movable by a user relative to the        housing from a first position to a second position, the trigger        being connected to the releasable latch for operating the        releasable latch by manipulation of the trigger (e.g. by        pressing, for example in order to release the releasable latch),        the trigger further being biased (e.g. by a compression spring)        towards the first position opposite to the second position        corresponding to release of the releasable latch; wherein the        drive train further includes a rotational strain sensing        arrangement which is configured to convert rotational strain        into an axial force or interlocking, the axial force or        interlocking being applied to the trigger by a mechanical        linkage to thereby prevent the trigger from returning to the        first position until the rotational strain acting on the        rotational strain sensing arrangement of the drive train reduces        below a predetermined threshold value.

According to the above general disclosure the drug delivery device mayimplement an expelling mechanism that indicates its state with regard tostalling to the user by means of the position of the trigger when thereleasable latch is released by the user. If the expelling mechanismallows the trigger to entirely return to its initial rest position(first position) which is different from the second position, forexample with regard to the longitudinal axis of the drug deliverydevice, the user knows that there is no residual torsion within thedrive mechanism. This behavior may be achieved by detecting the extentof the residual rotational strain in the drive train wherein the triggerto return to its initial rest position only if the rotational strain isor decreases below a predetermined threshold value. In contrast, thecircumstance that the trigger is not or not fully returned to its firstposition is used to indicate to the user that there is a considerableamount of residual rotational strain (or torque) within the drivemechanism which is equivalent to a stalling condition.

In instances the first position of the trigger may be an extendedposition with regard to the housing and the second position may be aretracted position with regard to the housing. In another embodiment thefirst position is a retracted position and the second position is anextended position with regard to the housing. Thereby retracted meanseither fully or partly retracted with regard to the housing, for examplewith regard to the proximal end of the housing. In one embodiment theproximal end of the housing may be formed by a proximal end of a doseselector, e.g. a dose knob.

In one embodiment the mechanical linkage between the trigger and therotational strain sensing arrangement is configured to allow the triggerto leave the second position under any torque strain condition and tomove towards an intermediate position away from the second positionthereby causing re-engagement of the releasable latch. The intermediateposition is located between the first (initial) position and the secondposition.

In one embodiment the trigger is a button, which is axially pressed indistal direction for initiating dispensing of the selected dose.Alternatively, the trigger is a button which is axially pulled inproximal direction for initiating dispensing of the selected dose.

In a further embodiment the trigger is held in the second positionduring dispensing of the medicament dose and released or manually movedback by the user when the user finishes dose application. Sometimes, theuser releases or manually moves back the trigger when only part of thedialed dose is applied. In one embodiment the expelling mechanismcomprises a clutch spring which is adapted to drive the trigger from thesecond position to the first position after the user has released thetrigger via the drive sleeve providing that the residual torsion is lessthan the predefined value.

In another embodiment concerning the power transmission from themechanical energy reservoir to the lead screw the releasable latch islocated between the upstream interface and the rotational strain sensingarrangement or, alternatively, the latch is located between thedownstream interface and the rotational strain sensing arrangement. Inthe first case the trigger returned to the first position if thedispensing step is interrupted before the full pre-defined or dialeddose is expelled so that the residual rotational strain within thesystem is shown to the user. In the second case the trigger stayed inthe second position (and did not return to the first position) evenwithout stalling if the dispensing step is interrupted before the fullpre-defined or dialed dose is expelled showing to the user that thepre-defined or dialed dose is not fully expelled.

In one embodiment the drive train comprises a releasable latch (orclutch mechanism) which is released or disengaged by the movement of thetrigger from the first position to the second position in order to allowtransfer of rotational energy from the upstream interface to thedownstream interface and to dispense the selected dose of the medicamentfrom the medicament reservoir. The latch may be reengaged if the triggerat least partly returns (i.e. returns at least part of the way) from thesecond position to the first position. The latch maybe—accordingly—released or disengaged if the trigger at least partlyreturns (i.e. returns at least part of the way) from the second positionto the first position, i.e. to an intermediate position.

In one embodiment the drive train may further include a user-settableend stop limiter, for example a dose knob, configured for enabling auser to restrict the amount of rotation that is transferred by the drivetrain upon release of the releasable latch to a user-determined angle.In this case the amount of liquid medicament formulation expelled duringdose dispensing step initiated by the trigger may be selected by theuser. For example, the mechanical energy reservoir (e.g. a torsionspring) is coupled to the end stop limiter such as to translate settingof the end stop limiter into immediate energizing of the energyreservoir to an extent corresponding to the rotational angle selected bythe user. This embodiment realizes a wind up mechanism used, forexample, during dose setting, which loads energy into the energyreservoir, which is sufficient and necessary for dispensing the setdose. Alternatively, the amount of rotation that is transferred to thedrive train upon release of the releasable latch is pre-determined, forexample by the prestressing of a torsion spring.

In one embodiment, which is cost-effective in realization, the drivetrain comprises a drive sleeve and the downstream interface of the drivetrain comprises a spline at the drive sleeve, the first splinedconnection formed by the spline and the rotational input interface beinglocated at an axial distance relative to the treaded nut, wherein therotational strain sensing arrangement includes a locking ring beingmaintained in a rotational fixed relation to the lead screw by a secondsplined connection at a position located between the first splinedconnection and the threaded nut, the locking ring and the drive sleeveimplementing angular dependent axial keying to thereby limit relativeaxial travel between these parts when the advancing angle of the drivesleeve relative to the locking nut due to torsional deformation exceedsa predefined threshold angle.

In one embodiment the lead screw is flexible. In case that there is aresidual rotational strain this rotational strain twists/distorts thelead screw due to its flexibility. Accordingly, the locking ring whichis rotationally constrained to the lead screw is rotated about the sameamount relative to the drive sleeve. The locking ring is splined to thelead screw and axially constrained to the housing. The relative rotationof the locking ring with regard to the drive sleeve is used to preventmovement of the drive sleeve in an axial direction and with it preventmovement of the trigger into the first position.

In a further embodiment the mechanical linkage between the trigger andthe rotational strain sensing arrangement includes a mechanicalconnection that at least partly limits the travel of the triggeraccording to the limitation occurring in the angular dependent axialkeying between the drive sleeve and the locking nut. In one embodimentthe trigger is mechanically connected to an axial movement of the drivesleeve and/or the locking nut. This means that the connection betweenthe trigger and the drive sleeve and/or the locking nut is such that anaxial movement of the drive sleeve and/or the locking nut drives thetrigger in axial direction. In one case the locking nut may be axiallyfixed to the housing but alternatively, the locking nut may be axiallymovable with regard to the housing.

In one embodiment the angular dependent axial keying comprises a slottedengagement of a radial pin rotationally fixed at the locking nut and thedrive sleeve in an L-shaped track to thereby restrict relative axialtravel between the locking nut and the drive sleeve according therelative angular position thereof.

In an alternative embodiment, if the lead screw is not (sufficiently)flexible, the drive sleeve comprises a flexible arm with a splinefeature guided within an axial spline of the lead screw, wherein therotational strain of the energy reservoir provided by the rotationalinterface deflects the flexible arm into a direction perpendicular tothe axial direction, i.e. a tangential direction. Accordingly, thetorsional deformation occurs in this case in the flexible arm.Analogously to the above embodiment, the first element is a locking ringrotationally constrained to the lead screw and the second element is thedrive sleeve. In this embodiment the flexibility of the lead screwcausing relative rotation of the lead screw and the drive sleeve isreplaced by the flexibility of the arm of the drive sleeve guided withinthe axial spline of the lead screw. The flexible arm is elongated alongthe longitudinal direction of the device and the drive sleeve and may betwisted into a direction perpendicular to the longitudinal direction(tangential direction), for example around the circumference of thedrive sleeve. In one embodiment the flexible arm may be formed by arespective cutout within the drive sleeve. The flexible arm isaccommodated within the plane of the drive sleeve body, wherein thespline feature extends from the inner surface of the flexible arm.

With regard to both above embodiments, for example, the rotationalstrain sensing arrangement comprises a locking ring and a radial pinprovided at the outer surface of the locking ring which is moved withina first axial section of an L-shaped track of the drive sleeve caused bythe movement of the trigger relative to the housing, wherein the drivesleeve is axially coupled to the trigger during initiating dispensing ofthe selected dose. The radial pin of the locking ring is additionallymoved within a second circumferential (tangential) section of theL-shaped path (e.g. slot) running perpendicular to the first sectioncaused by the deflection caused by the rotational strain of the energyreservoir. The radial pin of the locking ring stays within the secondcircumferential section if the rotational strain is not released at theend of the dispensing step. Thereby, the return movement of the drivesleeve is prevented, so that the trigger is not forced into the initialposition. In this embodiment, the connection between the drive train andthe lead screw formed by the downstream interface and the rotationalinput interface, e.g. a splined connection, is located an appreciabledistance from the locking ring radial pin.

In another embodiment, the second section of the L-shaped path of thedrive sleeve allows a movement of the radial pin in an axial direction,for example by widening the second section of the L-shaped path in axialdirection. This allows movement of the drive sleeve into the proximaldirection if the radial pin is in the second section of the L-shapedtrack so that a releasable latch is reengaged thereby preventingtransfer of rotational energy from the upstream interface to thedownstream interface. Thereby, the user is allowed to interrupt thedispense action of the device part way through dispense by removing theforce they applied to the trigger, but the trigger does not move fullyback to its initial position, preferably to an intermediate position.

In one embodiment the strain sensing arrangement of the drive traincomprises a helical interface for converting the rotational strain intoan axial strain. For example, the helical interface may comprise aclutch plate having an outer spline and a proximal section of a numbersleeve having an inner spline, wherein at least one of the outer splineand the inner spline has an angled surface or edge, wherein the clutchplate is axially coupled to the trigger.

In one embodiment the mechanical linkage between the strain sensingarrangement and the trigger is configured to feed an axial forceproduced by the strain sensing arrangement to the trigger to therebycompensate the biasing force until the rotational strain acting on thestrain sensing arrangement of the drive train reduces below thepredetermined threshold value. For example, the resulting axial loadproduced by the helical interface causes the clutch plate to held in thedistal position and thereby prevents the clutch spring from returningthe trigger to the first position even if the trigger is released by theuser as long as the rotational strain does not reduce below thepredetermined threshold value.

In this embodiment the proximal section of the number sleeve may form aseparate element which is fixedly attached to the distal section of thenumber sleeve. Alternatively, the proximal and the distal part of thenumber sleeve are integrally formed. The inner spline of the numbersleeve and the outer spline of the clutch plate run parallel to thelongitudinal axis of the drug delivery device and one of the spline runsat least partially under a small angle (e.g. lower than or equal to 30°)to the longitudinal axis if the spline edge and the longitudinal axisare projected into a circumferential plane around the longitudinal axisof the drug delivery device. For example, the inner spline of the numbersleeve and the outer spline of the clutch plate mesh with one anothersuch that the clutch plate is clamped by the inner spline of the numbersleeve as long as there is the above defined residual torque. Whenmeshing with one another the clutch plate and the number sleeve rotaterelative to one another. The clutch plate is, for example, a sleeve-likeor ring-like component and clutched to the drive sleeve, preferably viaa ratchet interface. Further, the clutch plate may provide a clicker armfor interaction with ratchet features of the trigger.

In another embodiment the angled surface or edge of the inner splinecomprises an angled surface with a first inner spline section formed bythe proximal section of the number sleeve and a second inner splinesection formed by a distal section of the number sleeve. This embodimentallows the drive sleeve to move far enough to reengage the releasablelatch if the user, for example, releases the trigger, causing the dosedispense to be interrupted. The second inner spline section may runparallel to the longitudinal axis of the drug delivery device, whereasthe first inner spline section has a small angle (e.g. lower than orequal to 30°) to the longitudinal axis if the spline edge and thelongitudinal axis are projected into a circumferential plane around thelongitudinal axis of the drug delivery device.

In an embodiment mechanical energy reservoir may comprise a clutchspring which may be formed as a compression spring. Preferably, theclutch spring is located axially interposed between the stationaryhousing component and the axially movable drive sleeve. The sleeve maycomprise latch features adapted to engage corresponding latch featuresof the releasable latch. Preferably, the latch forms a releasableratchet clutch suitable to couple and de-couple the sleeve and thethreaded nut. In another embodiment the latch features each form aseries of teeth. In a preferred embodiment the clutch spring biases(actuates) the latch features into engagement. For example the latchfeatures may be rotationally constrained when engaged and free to rotaterelative to each other when released. The released state of the latchfeatures may include a condition where the latch features contact eachother, but are allowed to overhaul each other, i.e. the latch featuresslip. The axial position of the drive sleeve, clutch plate and triggeris defined by the action of the clutch spring, which applies a force onthe drive sleeve in the proximal direction.

The latch features may be in a releasable engagement allowing the latchfeatures to be overhauled against the bias of the clutch spring at leastin one rotational direction when the sleeve is in the proximal positionand that the latch features are rotationally constrained when the sleeveis in the distal position. For example, the latch features may eachcomprise a series of teeth, preferably saw-teeth, which are allowed toslip over each other if not pressed against each other too firmly. Inother words, the latch features may be overhauled against the bias ofthe clutch spring by allowing the sleeve and/or the other latch elementto translate axially against the force of the clutch spring. This mayresult in an oscillating axial movement of the sleeve and/or the latchelement due to continued disengagement and following re-engagement intothe next detent position. An audible click may be generated by thisre-engagement, and tactile feedback may be given by the change in torqueinput required.

In addition, the latch features may comprise teeth having a ramp angleallowing overhauling of the ratchet, e.g. for dose correction when usedin a drug delivery device. In other words, relative rotation of thesleeve and the clutch element is allowed in both directions when thespring arrangement is in the state or condition where the clutchfeatures and the corresponding clutch features are not rotationallyfixed.

Preferably, the latch features and the corresponding clutch featuresprovides a detented position between the sleeve and the latch elementcorresponding to each dose unit when used in a drug delivery device, andengage different ramped tooth angles during clockwise and anti-clockwiserelative rotation. This is especially useful if the spring arrangementfurther comprises a drive spring having a rotational force or torquewhich is reacted via the latch features and the corresponding latchfeatures from the clutch element and the sleeve to the housingcomponent.

The sleeve is preferably coupled (directly or indirectly) to the trigger(button) such that upon actuation of the trigger the sleeve istranslated against the bias of the clutch spring from the first proximalposition in which the sleeve is rotationally locked to the housingcomponent into the second distal position in which the sleeve isrotationally un-locked from the housing component. In other words, thereare two states of the sleeve, namely a state where the sleeve isrotationally locked to the housing component and a state where thesleeve is allowed to rotate relative to the housing component, which twostates are defined by the axial position of the sleeve relative to thehousing component. The sleeve is held in one of these states by theaction of the clutch spring as long as the trigger is not actuated todisplace the sleeve against the spring force. Preferably, upon releaseof the trigger the clutch spring translates the sleeve and the triggerinto the proximal position.

The clutch spring may be a compression spring, preferably an axiallyacting compression spring. As an alternative, the clutch spring may be atension spring. In instances the clutch spring may be a coil spring. Asan alternative, the clutch spring may be a spring washer or a block orsleeve made from an elastically deformable material like rubber.Although the clutch spring is referred to herein as a single spring, thepresent disclosure shall be understood to encompass embodiments of theclutch spring with more than one single spring element as well. Thespring elements, in instances, may be arranged in parallel or in series.

The latch element comprises latch features and may have the form of aplate or disk. As an alternative, the latch element may have the form ofa sleeve. The latch element is axially interposed between the sleeve andthe trigger such that axial movement of the trigger in a firstdirection, preferably in the distal direction, is transferred to thesleeve via the clutch element and axial movement in the opposite,preferably proximal, direction is transferred to the trigger via theclutch element. As an alternative, the latch element may be a unitarypart of the trigger. In a preferred embodiment the clutch element ispermanently or releasably coupled to further component parts of a drugdelivery device, for example a number sleeve and/or a dose settingmember. The latch element may be a multi-functional element having inaddition to the interface with the sleeve and the interface with thetrigger e.g. a clicker feature and/or at least one further interface.

The trigger is preferably a user operable element located proximallyfrom the sleeve and the clutch element. When used in a drug deliverydevice, the trigger may extend from the proximal end of the device and,preferably, does not change its axial position during dose setting. Thetrigger is preferably coupled to a user operable dose setting member andmay be releasably coupled to a number sleeve component and/or astationary housing component. In an alternative embodiment, the triggermay be part of a dose setting arrangement or may be the dose settingmember. The trigger may be a multi-functional element having in additionto the above features e.g. a clicker feature. In another embodiment thetrigger and/or the dose selector may comprise a detent feature that wassufficient to resist the weight of the trigger but not sufficient toresist the force of the clutch spring (applied to the trigger via thedrive sleeve and clutch plate). With this feature, the trigger wouldonly return to its first position when driven by the drive sleeve (e.g.via the clutch plate) in an unblocked needle condition and not under theaction of gravity.

The stationary housing is a fixed foundation for relative movements ofthe axially movable drive sleeve, the clutch element, the gauge elementand the trigger and for relative rotational movements, e.g. of thenumber sleeve, the drive sleeve and the lead screw. It may be part of amulti-component housing or may be the only housing component of a drugdelivery device. In a preferred embodiment, the housing comprises anaxial support or bearing for the clutch spring and means for releasablyengaging the sleeve. Preferably, the housing comprises one or moreteeth, for example a ring of teeth, engaging one or more correspondingteeth, preferably also a ring of teeth, of the sleeve depending on therelative axial position of the sleeve with respect to the housing. Inother words, the engagement means or teeth mesh and interlock in afirst, e.g. proximal, position of the sleeve relative to the housing andare disengaged, thus allowing relative rotation, in a second, e.g.distal, position of the sleeve relative to the housing. The means forreleasably engaging the sleeve, for example the ring of teeth, may beattached to a body insert which is a housing component fixedly attachedto the housing. The housing may be a multi-functional element having inaddition to the above features e.g. a clicker feature and/or aninterface to a lead screw.

In one embodiment the drive train may comprise an axially movable drivesleeve which is a tubular element and has, preferably at its distal end,an interface for releasable engagement with the housing component and,preferably at its proximal end, an interface for releasable engagementwith the releasable latch, namely latch features, for example a ring ofradially extending outer teeth. In addition, the sleeve comprises anaxial support or bearing for the clutch spring. The clutch spring may bearranged axially interposed between the housing component and the drivesleeve. In an alternative embodiment, the sleeve at least partlysurrounds the clutch spring or the clutch spring at least partlysurrounds the sleeve.

Preferably, the sleeve is a drive sleeve which is rotationallyconstrained to the lead screw, for example by a spline, which is inthreaded engagement with the stationary housing part, e.g. the threadednut. In other words, rotation of the drive sleeve relative to thehousing component causes rotation of the lead screw and, thus, axialdisplacement of the lead screw relative to the housing component. Thismay be used in a drug delivery device during dose dispensing to advancea piston in a cartridge to expel medication from the cartridge. Thesleeve may be a multi-functional element having in addition to the abovefeatures e.g. a clicker feature and/or an activation interface for aclicker.

A further aspect may be seen in the provision of several interfaces onthe axially movable drive sleeve. Preferably, the drive sleeve has theupstream interface for permanently rotationally constraining the drivesleeve and the lead screw. An interface in form of the latch may beprovided between the drive sleeve and the housing (or a housingcomponent) for rotationally constraining the drive sleeve and thehousing depending on the axial position of the drive sleeve and/or thebias of the clutch spring. Another interface (e.g. a splined toothinterface and/or a coupling via a clutch plate) may be provided betweenthe drive sleeve and the number sleeve (or a dose setting component) forrotationally constraining the drive sleeve and the number sleevedepending on the axial position of the drive sleeve. A fifth interfacemay be provided between the drive sleeve and the rotational strainsensing arrangement for generating a feedback upon the amount ofresidual rotational strain, preferably only at the end of dosedispensing, and depending on the axial position of the drive sleeve.

In a preferred embodiment, the mechanical reservoir comprises a torsionspring rotationally coupled to the number sleeve. The torsion spring(drive spring) may be prestrained and/or may be strained (charged) byrelative rotation between number sleeve and the housing. The torsionspring may be attached at one end to the housing component and/or anadditional housing component and at the other end to a component partcoupled to the latch feature. The torsion spring may be pre-wound uponassembly of a drug delivery device, such that it applies a torque to thenumber sleeve when the mechanism is at zero units dialled.

Providing a resilient drive member, such as a torsion spring, forgenerating the force or torque required for dose dispensing may reducethe user applied forces for dose dispensing. This may especially becomehelpful for users with impaired dexterity. In addition, the dialextension of the known manually driven devices, which is a result of therequired dispensing stroke, may be omitted by providing the resilientmember because merely a small triggering stroke may be necessary forreleasing the resilient member.

In a drug delivery device at least one dose setting member may beprovided that can be operated to set a dose, wherein actuation of thetrigger causes dispensing of the set dose. Preferably, the operation ofthe at least one dose setting member strains the drive spring andactuation of the trigger allows the drive spring to relax and therebyrotate the number sleeve, the drive sleeve and the lead screw relativeto the housing component which causes the lead screw to advance in thedistal direction relative to the housing component.

The drug delivery device may further comprise the housing, having afirst aperture, the number sleeve positioned within the housing androtatable with respect to the housing during dose setting and duringdose dispensing, and a gauge element, which is interposed between thehousing and the number sleeve. Preferably, the gauge element has asecond aperture, which is positioned with respect to the first apertureof the housing such that at least a part of the number sleeve is visiblethrough the first and second apertures. The gauge element may be axiallyguided within the housing and in threaded engagement with the numbersleeve such that rotation of the number sleeve causes an axialdisplacement of the gauge element.

The position of the gauge element may thus be used to identify theactually set and/or dispensed dose. Different colours of sections of thegauge member may facilitate identifying the set and/or dispensed dosewithout reading numbers, symbols or the like on a display. As the gaugeelement is in threaded engagement with the number sleeve, rotation ofthe number sleeve causes an axial displacement of the gauge elementrelative to the number sleeve and relative to the housing. The gaugeelement may have the form of a shield or strip extending in thelongitudinal direction of the device. As an alternative, the gaugeelement may be a sleeve. In an embodiment, the number sleeve is markedwith a sequence of numbers or symbols and the gauge element comprises anaperture. With the number sleeve located radially inwards of the gaugeelement, this allows that at least one of the numbers or symbols on thenumber sleeve is visible through the aperture or window. In other words,the gauge element may be used to shield or cover a portion of the numbersleeve and to allow viewing only on a limited portion of the numbersleeve. This function may be in addition to the gauge element itselfbeing suitable for identifying or indicating the actually set and/ordispensed dose.

In a preferred embodiment, the number sleeve, during dose setting, isadapted to undergo a mere rotational movement within the housing andrelative to the housing. In other words, the number sleeve does notperform a translational movement during dose setting. This prevents theneed for the number sleeve to be wound out of the housing or for thehousing to be prolonged for covering the number sleeve within thehousing.

It is preferred if the device is suitable for dispensing variable,user-selectable, doses of medicament. The device may be a disposabledevice, i.e. a device which does not provide for an exchange of an emptycartridge.

According to a preferred embodiment, the drug delivery device comprisesa limiter mechanism defining a maximum settable dose and a minimumsettable dose. Typically, the minimum settable dose is zero (0 IU ofinsulin formulation), such that the limiter stops the device at the endof dose dispensing. The maximum settable dose, for example 60, 80 or 120IU of insulin formulation, may be limited to reduce the risk ofoverdosage and to avoid the additional spring torque needed fordispensing very high doses, while still being suitable for a wide rangeof patients needing different dose sizes. Preferably, the limits for theminimum dose and the maximum dose are provided by hard stop features.The limiter mechanism may comprise a first rotational stop on the numbersleeve and a first counter stop on the gauge element, which abut in theminimum dose (zero) position, and a second rotational stop on the numbersleeve and a second counter stop on the gauge element, which abut in themaximum dose position. As the number sleeve rotates relative to thegauge element during dose setting and during dose dispensing, these twocomponents are suitable to form a reliable and robust limiter mechanism.

The drug delivery device may further comprise a last dose protectionmechanism for preventing the setting of a dose, which exceeds the amountof liquid left in a cartridge. This has the advantage that the userknows how much will be delivered before starting the dose delivery. Italso ensures that dose delivery stops in a controlled manner without thebung entering the neck portion of the cartridge where the diameter issmaller which may result in an underdose. In a preferred embodiment,this last dose protection mechanism only detects the medicamentremaining in the cartridge when the cartridge contains less than themaximum dose (e.g. 120 IU). For example, the last dose protectionmechanism comprises a nut member interposed between the drive member anda component which rotates during dose setting and dose dispensing. Thecomponent which rotates during dose setting and dose dispensing may bethe number sleeve or a dial sleeve rotationally constrained to thenumber sleeve. In a preferred embodiment, the number sleeve and/or adial sleeve rotate during dose setting and during dose dispensing,whereas the drive member only rotates during dose dispensing togetherwith the number sleeve and/or the dial sleeve. Thus, in this embodiment,the nut member will only move axially during dose setting and willremain stationary with respect to these components during dosedispensing. Preferably, the nut member is threaded to the drive memberand splined to the number sleeve and/or the dial sleeve. As analternative, the nut member may be threaded to the number sleeve and/orthe dial sleeve and may be splined to the drive member. The nut membermay be a full nut or a part thereof, e.g. a half nut.

The injection device may comprise more than one clicker mechanism forgenerating a tactile and/or audible feedback. During dose settingre-engagement of the clutch features of the (drive) sleeve and thecorresponding clutch features of the clutch element may generate anaudible and/or tactile feedback. For example, a tactile feedback duringdose dispense may be provided by ratchet features located on the triggerand interacting at least during dose dispensing with a clicker armlocated on the clutch element. As the clutch element rotates relative tothe trigger during dispense, this relative rotation may be used togenerate a feedback signal. Preferably, the trigger is rotationallylocked to the housing or housing component during dose dispensing.

Preferably, the piston rod (lead screw) advances by a fixed displacementfor each revolution of the movable (drive) sleeve. In other embodiments,the rate of displacement may vary. For example, the lead screw mayadvance a large displacement per revolution to dispense a first amountof medicament from the cartridge and then a smaller displacement perrevolution to dispense the rest of the cartridge. This is advantageous,as it can compensate for the fact that the first dose dispensed from thecartridge often has a lower volume than other doses, for a givendisplacement of the mechanism. If the pitch is equal on the threads ofthe housing and the lead screw, the lead screw advances a fixed amountfor every revolution of the movable sleeve. However, if in analternative embodiment the first turn of the thread on the lead screwhas a large pitch and the other turns have a small pitch, during thefirst revolution the lead screw displacement depends on the large pitchof the first turn of thread on the lead screw, so it displaces a largeamount per revolution. For subsequent revolutions the lead screwdisplacement depends on the smaller pitch of the lead screw thread, soit displaces a smaller amount. If, in a further embodiment, the housingthread has a larger pitch than the lead screw, during the firstrevolution, the lead screw displacement depends on the pitch of thehousing thread, so it displaces a large amount per revolution. Forsubsequent revolutions the lead screw displacement depends on the pitchof the lead screw thread, so it displaces a smaller amount.

The aperture in the housing and/or the aperture in the gauge element maybe a simple opening. However, it is preferred if at least one apertureis closed by a window or lens which prevents intrusion of dirt and/ormay increase legibility of e.g. numbers on the number sleeve, forexample due to a magnification.

According to an embodiment the number sleeve is clipped to the housingat the distal end. This reduces the geometric tolerances for the gaugeposition. In other words, the number sleeve is preferably axially fixedrelative to the housing but allowed to rotate relative thereto.

Preferably, the drive sleeve is clipped inside the number sleeve toretain it during subsequent assembly steps. In an alternativeembodiment, the drive sleeve is clipped to the housing instead to retainit during subsequent assembly steps. In both embodiments, the drivesleeve is free to move beyond its assembled position when the trigger ispressed. The clips prevent movement in the disassembly direction, but donot prevent further movement, e.g. for dispense.

The lens and the window in the gauge may be incorporated into thehousing using a ‘twin-shot’ moulding technology. For example, they aremoulded during a ‘first shot’ in a translucent material, and the outercover of the housing is moulded during a ‘second shot’ in an opaquematerial.

If there is only one threaded portion on the gauge element this reducesthe length of this component.

Preferably, the tooth geometry on the clutch plate and the drive sleeveis chosen such that the dialling torque is low. Further, the clutchplate may comprise a dispense clicker which interferes with clickerteeth on the trigger.

The drug delivery device may comprise a cartridge containing a liquidmedicament formulation. The term “medicament” or “medicamentformulation”, as used herein, means a pharmaceutical formulationcontaining at least one pharmaceutically active compound,

wherein in one embodiment the pharmaceutically active compound has amolecular weight up to 1500 Da and/or is a peptide, a proteine, apolysaccharide, a vaccine, a DNA, a RNA, an enzyme, an antibody or afragment thereof, a hormone or an oligonucleotide, or a mixture of theabove-mentioned pharmaceutically active compound,

wherein in a further embodiment the pharmaceutically active compound isuseful for the treatment and/or prophylaxis of diabetes mellitus orcomplications associated with diabetes mellitus such as diabeticretinopathy, thromboembolism disorders such as deep vein or pulmonarythromboembolism, acute coronary syndrome (ACS), angina, myocardialinfarction, cancer, macular degeneration, inflammation, hay fever,atherosclerosis and/or rheumatoid arthritis,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one peptide for the treatment and/or prophylaxis ofdiabetes mellitus or complications associated with diabetes mellitussuch as diabetic retinopathy,

wherein in a further embodiment the pharmaceutically active compoundcomprises at least one human insulin or a human insulin analogue orderivative, glucagon-like peptide (GLP-1) or an analogue or derivativethereof, or exendin-3 or exendin-4 or an analogue or derivative ofexendin-3 or exendin-4.

Insulin analogues are for example Gly(A21), Arg(B31), Arg(B32) humaninsulin; Lys(B3), Glu(B29) human insulin; Lys(B28), Pro(B29) humaninsulin; Asp(B28) human insulin; human insulin, wherein proline inposition B28 is replaced by Asp, Lys, Leu, Val or Ala and wherein inposition B29 Lys may be replaced by Pro; Ala(B26) human insulin;Des(B28-B30) human insulin; Des(B27) human insulin and Des(B30) humaninsulin.

Insulin derivates are for example B29-N-myristoyl-des(B30) humaninsulin; B29-N-palmitoyl-des(B30) human insulin; B29-N-myristoyl humaninsulin; B29-N-palmitoyl human insulin; B28-N-myristoyl LysB28ProB29human insulin; B28-N-palmitoyl-LysB28ProB29 human insulin;B30-N-myristoyl-ThrB29LysB30 human insulin; B30-N-palmitoyl-ThrB29LysB30human insulin; B29-N-(N-palmitoyl-Y-glutamyl)-des(B30) human insulin;B29-N-(N-lithocholyl-Y-glutamyl)-des(B30) human insulin;B29-N-(ω-carboxyheptadecanoyl)-des(B30) human insulin andB29-N-(ω-carboxyheptadecanoyl) human insulin.

Exendin-4 for example means Exendin-4(1-39), a peptide of the sequenceH-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH2.

Exendin-4 derivatives are for example selected from the following listof compounds:

H-(Lys)4-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

H-(Lys)5-des Pro36, des Pro37 Exendin-4(1-39)-NH2,

des Pro36 Exendin-4(1-39),

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39); or

des Pro36 [Asp28] Exendin-4(1-39),

des Pro36 [IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14, IsoAsp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Trp(O2)25, IsoAsp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, Asp28] Exendin-4(1-39),

des Pro36 [Met(O)14 Trp(O2)25, IsoAsp28] Exendin-4(1-39),

wherein the group-Lys6-NH2 may be bound to the C-terminus of theExendin-4 derivative;

or an Exendin-4 derivative of the sequence

des Pro36 Exendin-4(1-39)-Lys6-NH2 (AVE0010),

H-(Lys)6-des Pro36 [Asp28] Exendin-4(1-39)-Lys6-NH2,

des Asp28 Pro36, Pro37, Pro38Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro38 [Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Trp(O2)25] Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36 [Met(O)14, Asp28] Exendin-4(1-39)-Lys6-NH2,

des Met(O)14 Asp28 Pro36, Pro37, Pro38 Exendin-4(1-39)-NH2,

H-(Lys)6-desPro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Asn-(Glu)5 des Pro36, Pro37, Pro38 [Met(O)14, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-Lys6-des Pro36 [Met(O)14, Trp(O2)25, Asp28] Exendin-4(1-39)-Lys6-NH2,

H-des Asp28 Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25]Exendin-4(1-39)-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Asp28] Exendin-4(1-39)-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-NH2,

des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2,

H-(Lys)6-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(S1-39)-(Lys)6-NH2,

H-Asn-(Glu)5-des Pro36, Pro37, Pro38 [Met(O)14, Trp(O2)25, Asp28]Exendin-4(1-39)-(Lys)6-NH2;

or a pharmaceutically acceptable salt or solvate of any one of theafore-mentioned Exendin-4 derivative.

Hormones are for example hypophysis hormones or hypothalamus hormones orregulatory active peptides and their antagonists as listed in RoteListe, ed. 2008, Chapter 50, such as Gonadotropine (Follitropin,Lutropin, Choriongonadotropin, Menotropin), Somatropine (Somatropin),Desmopressin, Terlipressin, Gonadorelin, Triptorelin, Leuprorelin,Buserelin, Nafarelin, Goserelin.

A polysaccharide is for example a glucosaminoglycane, a hyaluronic acid,a heparin, a low molecular weight heparin or an ultra low molecularweight heparin or a derivative thereof, or a sulphated, e.g. apoly-sulphated form of the above-mentioned polysaccharides, and/or apharmaceutically acceptable salt thereof. An example of apharmaceutically acceptable salt of a poly-sulphated low molecularweight heparin is enoxaparin sodium.

Antibodies are globular plasma proteins (˜150 kDa) that are also knownas immunoglobulins which share a basic structure. As they have sugarchains added to amino acid residues, they are glycoproteins. The basicfunctional unit of each antibody is an immunoglobulin (Ig) monomer(containing only one Ig unit); secreted antibodies can also be dimericwith two Ig units as with IgA, tetrameric with four Ig units liketeleost fish IgM, or pentameric with five Ig units, like mammalian IgM.

The Ig monomer is a “Y”-shaped molecule that consists of fourpolypeptide chains; two identical heavy chains and two identical lightchains connected by disulfide bonds between cysteine residues. Eachheavy chain is about 440 amino acids long; each light chain is about 220amino acids long. Heavy and light chains each contain intrachaindisulfide bonds which stabilize their folding. Each chain is composed ofstructural domains called Ig domains. These domains contain about 70-110amino acids and are classified into different categories (for example,variable or V, and constant or C) according to their size and function.They have a characteristic immunoglobulin fold in which two β sheetscreate a “sandwich” shape, held together by interactions betweenconserved cysteines and other charged amino acids.

There are five types of mammalian Ig heavy chain denoted by α, δ, ε, γ,and μ. The type of heavy chain present defines the isotype of antibody;these chains are found in IgA, IgD, IgE, IgG, and IgM antibodies,respectively.

Distinct heavy chains differ in size and composition; α and γ containapproximately 450 amino acids and δ approximately 500 amino acids, whileμ and ε have approximately 550 amino acids. Each heavy chain has tworegions, the constant region (CH) and the variable region (VH). In onespecies, the constant region is essentially identical in all antibodiesof the same isotype, but differs in antibodies of different isotypes.Heavy chains γ, α and δ have a constant region composed of three tandemIg domains, and a hinge region for added flexibility; heavy chains μ andε have a constant region composed of four immunoglobulin domains. Thevariable region of the heavy chain differs in antibodies produced bydifferent B cells, but is the same for all antibodies produced by asingle B cell or B cell clone. The variable region of each heavy chainis approximately 110 amino acids long and is composed of a single Igdomain.

In mammals, there are two types of immunoglobulin light chain denoted byλ and κ. A light chain has two successive domains: one constant domain(CL) and one variable domain (VL). The approximate length of a lightchain is 211 to 217 amino acids. Each antibody contains two light chainsthat are always identical; only one type of light chain, κ or λ, ispresent per antibody in mammals.

Although the general structure of all antibodies is very similar, theunique property of a given antibody is determined by the variable (V)regions, as detailed above. More specifically, variable loops, threeeach the light (VL) and three on the heavy (VH) chain, are responsiblefor binding to the antigen, i.e. for its antigen specificity. Theseloops are referred to as the Complementarity Determining Regions (CDRs).Because CDRs from both VH and VL domains contribute to theantigen-binding site, it is the combination of the heavy and the lightchains, and not either alone, that determines the final antigenspecificity.

An “antibody fragment” contains at least one antigen binding fragment asdefined above, and exhibits essentially the same function andspecificity as the complete antibody of which the fragment is derivedfrom. Limited proteolytic digestion with papain cleaves the Ig prototypeinto three fragments. Two identical amino terminal fragments, eachcontaining one entire L chain and about half an H chain, are the antigenbinding fragments (Fab). The third fragment, similar in size butcontaining the carboxyl terminal half of both heavy chains with theirinterchain disulfide bond, is the crystalizable fragment (Fc). The Fccontains carbohydrates, complement-binding, and FcR-binding sites.Limited pepsin digestion yields a single F(ab′)2 fragment containingboth Fab pieces and the hinge region, including the H-H interchaindisulfide bond. F(ab′)2 is divalent for antigen binding. The disulfidebond of F(ab′)2 may be cleaved in order to obtain Fab′. Moreover, thevariable regions of the heavy and light chains can be fused together toform a single chain variable fragment (scFv).

Pharmaceutically acceptable salts are for example acid addition saltsand basic salts. Acid addition salts are e.g. HCl or HBr salts. Basicsalts are e.g. salts having a cation selected from alkali or alkaline,e.g. Na+, or K+, or Ca2+, or an ammonium ion N+(R1)(R2)(R3)(R4),

wherein R1 to R4 independently of each other mean: hydrogen, anoptionally substituted C1-C6-alkyl group, an optionally substitutedC2-C6-alkenyl group, an optionally substituted C6-C10-aryl group, or anoptionally substituted C6-C10-heteroaryl group. Further examples ofpharmaceutically acceptable salts are described in “Remington'sPharmaceutical Sciences” 17. ed. Alfonso R. Gennaro (Ed.), MarkPublishing Company, Easton, Pa., U.S.A., 1985 and in Encyclopedia ofPharmaceutical Technology.

Pharmaceutically acceptable solvates are for example hydrates.

BRIEF DESCRIPTION OF THE FIGURES

Non-limiting, exemplary embodiments will now be described with referenceto the accompanying drawings, in which:

FIG. 1 shows a top view of a first embodiment of a drug delivery devicein the minimum dose position;

FIG. 2 shows an exploded view of the components of the device of FIG. 1;

FIG. 3 shows a sectional view of the device of FIG. 1;

FIG. 4a shows an enlarged sectional view of a detail of the device ofFIG. 1 in the dose setting mode;

FIG. 4b shows an enlarged sectional view of a detail of the device ofFIG. 1 in the dose dispensing mode;

FIG. 5 shows an interface between the number sleeve and the trigger ofthe device of FIG. 1;

FIG. 6 shows an interface between the housing and the trigger of thedevice of FIG. 1;

FIGS. 7a, b show an interface between the number sleeve and the drivesleeve of the device of FIG. 1 in the dose setting mode and in the dosedispensing mode;

FIG. 8 shows an interface between the lead screw and a bearing of thedevice of FIG. 1;

FIG. 9 shows an interface between the clutch plate and the trigger ofthe device of FIG. 1;

FIG. 10 shows in a sectional view the components of an end of doseclicker of the device of FIG. 1;

FIGS. 11a-c show in enlarged views the sequence of generating a click atthe end of dose dispensing of the device of FIG. 1;

FIGS. 12a-c show in enlarged sectional views the sequence of generatinga click at the end of dose dispensing of the device of FIG. 1;

FIG. 13 shows the gauge element of the device of FIG. 1;

FIG. 14 shows a portion of the number sleeve of the device of FIG. 1;

FIG. 15 shows a further portion of the number sleeve of the device ofFIG. 1;

FIG. 16 shows a portion of the drive spring of the device of FIG. 1;

FIGS. 17a, b show top views of the device of FIG. 1 with 0 units dialledand with 96 units dialled;

FIG. 18 shows an interface between the housing and the drive sleeve ofthe device of FIG. 1;

FIG. 19 shows an interface between the clutch plate and the drive sleeveof the device of FIG. 1;

FIG. 20 shows a last dose mechanism of the device of FIG. 1;

FIG. 21 shows the torsion spring of the device of FIG. 1;

FIG. 22 shows an enlarged sectional view of a detail of the device ofFIG. 1 in the zero dose position and in the dose dialling mode;

FIG. 23 shows the enlarged sectional view of FIG. 22 in the dosedispensing mode (first step);

FIG. 24 shows the enlarged sectional view of FIG. 22 in the dosedispensing mode (second step);

FIG. 25 shows an enlarged sectional view of a detail of a secondembodiment of a drug delivery device in the zero dose position and inthe dose dialling mode;

FIGS. 26,26 a show an enlarged sectional view of a detail of a thirdembodiment of a drug delivery device in the zero dose position and inthe dose dialling mode;

FIGS. 27,27 a show the enlarged sectional view of FIG. 26 in the dosedispensing mode;

FIG. 28 shows an enlarged sectional view of a detail at the proximal endof a fourth embodiment of a drug delivery device in the dose dispensingmode;

FIG. 29 shows an enlarged sectional view of a detail at the proximal endof a fifth embodiment of a drug delivery device in the dose dispensingmode;

FIG. 30 shows a top view of the device of FIG. 1 after dose dispensingshowing blocked needle; and

FIG. 31 shows a top view of the device of FIG. 1 after dose dispensingshowing correct injection with no residual torque.

DETAILED DESCRIPTION

FIG. 1 shows a drug delivery device in the form of an injection pen. Thedevice has a distal end (left end in FIG. 1) and a proximal end (rightend in FIG. 1). The component parts of the drug delivery device areshown in FIG. 2. The drug delivery device comprises a body or housing10, a cartridge holder 20, a lead screw (piston rod) 30, a drive sleeve40, a nut 50, a dose indicator (number sleeve) 60, a trigger in form ofa button 70, a dial grip or dose selector 80, a torsion spring 90, acartridge 100, a gauge element 110, a clutch plate 120, a clutch spring130 and a bearing 140. A needle arrangement (not shown) with a needlehub and a needle cover may be provided as additional components, whichcan be exchanged as explained above. All components are locatedconcentrically about a common principal axis I of the mechanism which isshown in FIG. 3.

The housing 10 or body is a generally tubular element having a proximalend with an enlarged diameter. The housing 10 provides location for thecartridge 100 comprising a liquid medicament formulation and cartridgeholder 20, windows 11 a, 11 b for viewing the dose number on the numbersleeve 60 and the gauge element 110, and a feature on its externalsurface, e.g. a circumferential groove, to axially retain the doseselector 80 forming an end stop limiter. A flange-like or cylindricalinner wall 12 of the housing 10 comprises an inner thread engaging thelead screw 30. The housing 10 further has at least one internal, axiallyorientated slot or the like for axially guiding the gauge element 110.In the embodiment shown in the Figures, the distal end is provided withan axially extending strip 13 partly overlapping cartridge holder 20.The Figures depict the housing 10 as a single housing component.However, the housing 10 could comprise two or more housing componentswhich may be permanently attached to each other during assembly of thedevice.

The cartridge holder 20 is located at the distal side of housing 10 andpermanently attached thereto. The cartridge holder may be a transparentor translucent component which is tubular to receive cartridge 100. Thedistal end of cartridge holder 20 may be provided with means forattaching a needle arrangement. A removable cap (not shown) may beprovided to fit over the cartridge holder 20 and may be retained viaclip features on the housing 10.

The lead screw 30 is rotationally constrained to the drive sleeve 40 viaa splined interface. When rotated, the lead screw 30 is forced to moveaxially relative to the drive sleeve 40, through its threaded interfacewith the inner wall 12 of housing 10 forming a threaded nut.

The lead screw 30 is an elongate member with an outer thread 31 (FIG. 4a) engaging the corresponding thread of the inner wall 12 of housing 10.The thread 31 may have a large lead-in, for example a wedge shape form,at its distal end to engage a corresponding housing thread form on thefirst rotation. At its distal end (see FIG. 8), the lead screw 30 isprovided with an interface for clip attachment of the bearing 140. Inthe present embodiment, this interface comprises two clip arms 32extending in the distal direction defining an insertion space betweenthem for insertion of a bearing 140 interface. As an alternative, theinterface may comprise only one single clip arm extending more than 180°about the longitudinal axis, or may comprise one or several clip arms32. The clip arm(s) 32 may have a bent form with a recessed clip portionas shown in FIG. 8. Preferably, the clip arm(s) form a cylindrical outerface having a diameter equal to or smaller than the outer diameter ofthe lead screw 30 at the base of the groove (flute base) of the outerthread 31. A concave contact surface 33 is provided between the cliparms 32 for abutment of a corresponding portion of bearing 140 (convexcontact surface 143).

The injection device provides a drive train comprising the drive sleeve40 which is a hollow member surrounding the lead screw 30 and arrangedwithin number sleeve 60. It extends from an interface with the clutchplate 120 to the contact with the clutch spring 130. The drive sleeve 40is axially movable relative to the housing 10, the lead screw 30 and thenumber sleeve 60 in the distal direction against the bias of clutchspring 130 and in the opposite proximal direction under the bias ofclutch spring 130.

The lead screw 30 comprises a longitudinal (axial) groove 35 which formsa splined connection with a longitudinal (axial) spline 49 of the drivesleeve 40 in order to rotationally constrict the lead screw 30 to thedrive sleeve 40 but to allow axial movement of the lead screw 30 withregard to the drive sleeve 40. The groove 35 is also referred to asrotational input interface whereas the spline 49 forms a downstreaminterface of the drive sleeve.

A splined tooth interface with the housing 10 (also referred to asreleasable latch) prevents rotation of the drive sleeve 40 during dosesetting. This interface which is shown in FIG. 18 in detail comprises aring of radially extending outer teeth 41 at the distal end of drivesleeve 40 and corresponding radially extending inner teeth 14 of thehousing component 10. When the button (trigger) 70 is pressed, thesedrive sleeve 40 to housing 10 spline teeth 14, 41 are disengagedallowing the drive sleeve 40 to rotate relative to housing 10 (forexample for dose dispense).

A further splined tooth interface with the number sleeve 60 is notengaged during dialling, but engages when the button 70 is pressed,preventing relative rotation between the drive sleeve 40 and numbersleeve 60 during dispense. In the preferred embodiment shown in FIGS. 7aand 7b this interface comprises inwardly directed splines 61 on a flange62 on the inner surface of the number sleeve 60 and a ring of radiallyextending outer splines 42 of drive sleeve 40 (the splines 42 are alsoreferred to as upstream interface and the splines 61 are referred to asrotational interface). The corresponding splines 61, 42 are located onthe number sleeve 60 and the drive sleeve 40, respectively, such thataxial movement of the drive sleeve 40 relative to the (axially fixed)number sleeve 60 engages or disengages the splines to rotationallycouple or decouple the drive sleeve 40 and the number sleeve 60.

Preferably, the splines 61, 42 are arranged such that they are decoupledwhen teeth 41 of drive sleeve 40 and inner teeth 14 of housing component10 mesh and engage when teeth 41 and inner teeth 14 disengage. In apreferred embodiment the splines 61, 42 are longer in the axialdirection compared with teeth 41, 14. This allows engagement of thesplines 61, 42 shortly before disengagement of teeth 41, 14. In otherwords, the splines 61, 42 and the teeth 41, 14 are designed and arrangedsuch that actuation of the button 70 rotationally constrains the drivesleeve 40 to the number sleeve 60 before the drive sleeve 40 is allowedto rotate relative to housing 10. Similarly, as the button 70 isreleased after dose dispensing axial movement of the drive sleeve 40first rotationally constrains the drive sleeve 40 to the housing andthereafter decouples splines 61, 42. As an alternative to thecorresponding splines 61, 42 teeth may be provided. As a furtheralternative or in addition to splines 61, 42, drive sleeve 40 and numbersleeve 60 may be rotationally coupled to each other during dosedispensing via clutch plate 120.

An interface of the drive sleeve 40 which is shown in FIG. 19 comprisesa ring of ratchet teeth 43 located at the proximal end face of drivesleeve 40 and a ring of corresponding ratchet teeth 121 of clutch plate120.

The drive sleeve 40 has a threaded section 44 providing a helical trackfor the nut 50 (FIG. 20). In addition, a last dose abutment or stop 46is provided which may be the end of the thread 44 track or preferably arotational hard stop for interaction with a corresponding last dose stop51 of nut 50, thus limiting movement of the nut 50 on the thread 44. Atleast one longitudinal spline 49 engages a corresponding track 35 of thelead screw 30 (FIG. 10). Further, the drive sleeve 40 is provided with aramp 47 (FIG. 20) interacting with a clicker arm 67 (FIG. 10)9 when thedrive sleeve 40 is in its distal position during dose dispensing, i.e.when button 70 is depressed.

The last dose nut 50 is located between the number sleeve 60 and thedrive sleeve 40. It is rotationally constrained to the number sleeve 60,via a splined interface (splines 52 on nut 50). It moves along a helicalpath relative to the drive sleeve 40, via a threaded interface (thread44), when relative rotation occurs between the number sleeve 60 anddrive sleeve 40 which is during dialling only. This is shown in FIG. 20.As an alternative, the nut 50 may be splined to the drive sleeve 40 andthreaded to the number sleeve 60. In the embodiment shown in theFigures, the nut 50 is a full nut, but in alternative embodiments it maybe a half nut, i.e. a component extending approximately 180° around thecenter axis of the device. A last dose stop 51 is provided engaging stop46 of drive sleeve 40 when a dose is set corresponding to the remainingdispensable amount of liquid medicament formulation in the cartridge100.

The dose indicator or number sleeve 60 is a tubular element as shown inFIGS. 2 and 3. The number sleeve 60 is rotated during dose setting (viadose selector 80) and dose correction and during dose dispensing bytorsion spring 90. Together with gauge element 110 the number sleeve 60defines a zero position (‘at rest’) and a maximum dose position. Thus,the number sleeve 60 may be seen as a dose setting member.

For manufacturing reasons the number sleeve 60 of the embodiment shownin the Figures comprises a number sleeve lower 60 a which is rigidlyfixed to a number sleeve upper 60 b during assembly to form the numbersleeve 60. Number sleeve lower 60 a and number sleeve upper 60 b areseparate components only to simplify number sleeve 60 mould tooling andassembly. As an alternative, the number sleeve 60 may be a unitarycomponent. The number sleeve 60 is constrained to the housing 10 byfeatures towards the distal end to allow rotation but not translation.The number sleeve lower 60 a is marked with a sequence of numbers, whichare visible through the gauge element 110 and the opening 11 b in thehousing 10, to denote the dialled dose of medicament.

Further, the number sleeve lower 60 a has a portion with an outer thread63 (see FIG. 14) engaging the gauge element 110. End stops 64, 65 areprovided at the opposite ends of thread 63 to limit relative movementwith respect to the gauge element 110.

Clutch features which have the form of a ring of splines 66 in theembodiment shown in FIG. 5 are provided inwardly directed on numbersleeve lower 60 a for engagement with splines 73 of the button 70 duringdose setting and dose correction. A clicker arm 67 is provided on theouter surface of number sleeve 60 which interacts with the drive sleeve40 and the gauge member 110 for generating a feedback signal. Inaddition, the number sleeve lower 60 a is rotationally constrained tothe nut 50 and to the clutch plate 120 via a splined interfacecomprising at least one longitudinal spline at its inner surface.

An interface for attachment of the torsion spring 90 to the numbersleeve lower 60 a comprises large lead-ins and a groove feature with apocket or anchor point for receiving a first coil or hook portion of thespring. The groove has an end feature in the form of a ramp that is ininterference with the hook portion 91 of the spring. The design of thegroove is such that the spring 90 may be received within the pocketwithout interfering with the gauge element 110. The mechanical energyreservoir for driving the lead screw 30 during dose dispensing comprisesthe number sleeve 60 and the torsion spring 90.

The button (trigger) 70 which forms the proximal end of the device ispermanently splined to the dose selector 80. A central stem 71 (see FIG.4b ) extends distally from the proximal actuation face of the button 70.The stem 71 is provided with a flange 72 carrying the splines 73 forengagement with splines 66 of the number sleeve upper 60 b (FIG. 5).Thus, it is also splined via splines 66, 73 (FIG. 5) to the numbersleeve upper 60 b when the button 70 is not pressed, but this splineinterface is disconnected when the button 70 is pressed. The button 70has a discontinuous annular skirt with splines 74. When the button 70 ispressed, splines 74 on the button 70 engage with splines on the housing10 (FIG. 6), preventing rotation of the button 70 (and hence the doseselector 80) during dispense. These splines 74, 15 disengage when thebutton 70 is released, allowing a dose to be dialled. Further, a ring ofratchet teeth 75 is provided on the inner side of flange 72 (FIG. 9) forinteraction with clutch plate 120.

The dose selector 80 is axially constrained to the housing 10. It isrotationally constrained, via the splined interface, to the button 70.This splined interface which includes grooves interacting with splinefeatures formed by the annular skirt of button 70 remains engagedirrespective of the dose button 70 axial positions. The dose selector 80or dose dial grip is a sleeve-like component with a serrated outerskirt.

The torsion spring 90 is attached at its distal end to the housing 10and at the other end to the number sleeve 60. The torsion spring 90 islocated inside the number sleeve 60 and surrounds a distal portion ofthe drive sleeve 40. As shown in FIG. 21, the spring has a hook 91 atone end for attachment on the number sleeve 60. A similar hook end 92 isprovided at the opposite end for attachment on the housing 10. Thetorsion spring 90 is pre-wound upon assembly, such that it applies atorque to the number sleeve 60 when the mechanism is at zero unitsdialled. The action of rotating the dose selector 80, to set a dose,rotates the number sleeve 60 relative to the housing 10, and charges thetorsion spring 90 further.

The torsion spring 90 is formed from a helical wire with at least twodifferent pitches. In FIG. 21, both ends are formed from ‘closed’ coils93, i.e. the pitch equals the wire diameter and each coil contacts theadjacent coil. The central portion has ‘open’ coils 94, i.e. the coilsdo not contact each other.

The cartridge 100 is received in cartridge holder 20 (FIG. 3). Thecartridge 100 may be a glass ampoule having a moveable rubber bung 101at its proximal end. The distal end of cartridge 100 is provided with apierceable rubber seal which is held in place by a crimped annular metalband. In the embodiment depicted in the Figures, the cartridge 100 isfor example a standard 1.5 ml cartridge. The device is designed to bedisposable in that the cartridge 100 cannot be replaced by the user orhealth care professional. However, a reusable variant of the devicecould be provided by making the cartridge holder 20 removable andallowing backwinding of the lead screw 30 and the resetting of nut 50.

The gauge element 110 (FIG. 13) is constrained to prevent rotation butallow translation relative to the housing 10 via a splined interface.The gauge element 110 has a helical feature 111 on its inner surfacewhich engages with the helical thread 63 cut in the number sleeve 60such that rotation of the number sleeve 60 causes axial translation ofthe gauge element 110. This helical feature on the gauge element 110also creates stop abutments 112, 113 against the end stop 64, 65 of thehelical cut in the number sleeve 60 to limit the minimum and maximumdose that can be set.

The gauge element 110 has a generally plate or band like componenthaving a central aperture 114 or window and two flanges 115, 116extending on either side of the aperture. The flanges 115, 116 arepreferably not transparent and thus shield or cover the number sleeve60, whereas the aperture 114 or window allows viewing a portion of thenumber sleeve lower 60 a. Further, gauge element 110 has a cam 117 and arecess 118 (FIGS. 11a-12c ) interacting with the clicker arm 67 of thenumber sleeve 60 at the end of dose dispensing.

As can be seen in FIGS. 9 and 19, the clutch plate 120 is a sleeve-likeor ring-like component. The clutch plate 120 is splined to the numbersleeve 60 via outer splines 125. It is also coupled to the drive sleeve40 via a ratchet interface (ratchet teeth 43, 121). The ratchet providesa detent position between the number sleeve 60 and drive sleeve 40corresponding to each dose unit, and engages different ramped toothangles during clockwise and anti-clockwise relative rotation. A clickerarm 123 is provided on the clutch plate 120 for interaction with ratchetfeatures 75 of the button 70.

The clutch spring 130 is a compression spring. The axial position of thedrive sleeve 40, clutch plate 120 and button 70 is defined by the actionof the clutch spring 130, which applies a force on the drive sleeve 40in the proximal direction. This spring force is reacted via the drivesleeve 40, clutch plate 120, and button 70, and when ‘at rest’ it isfurther reacted through the dose selector 80 to the housing 10. Thespring force ensures that the ratchet interface (ratchet teeth 43, 121)is always engaged. In the ‘at rest’ position, it also ensures that thebutton splines 73 are engaged with the number sleeve splines 66, and thedrive sleeve teeth 41 are engaged with teeth 14 of the housing 10.

The bearing 140 (see FIG. 8) is axially constrained to the lead screw 30and acts on the bung 101 within the liquid medicament cartridge. It isaxially clipped to the lead screw 30, but free to rotate. The bearing140 comprises a disc 141 having a stem 142 extending in the proximaldirection. The stem 142 has at its proximal end a convex contact surface143. In addition, a recessed portion 144 is provided on the stem 142.The curvature of the convex contact surface 143 and the concave contactsurface 33 of the lead screw 30 is chosen such that the contact diameterbetween the bearing 140 and lead screw 30 is small to minimize thefrictional losses at this interface. The design of the clip interfacebetween bearing 140 and lead screw 30 permits the lead screw 30 to beassembled axially, from the proximal end and through the threadengagement to the housing 10, which simplifies assembly. In addition,this design allows a simple “open and shut” mould tooling for bothcomponents.

With the device in the ‘at rest’ condition as shown in FIGS. 4a and 17a, the number sleeve 60 is positioned against its zero dose abutment 64,113 with the gauge element 110 and the button 70 is not depressed. Dosemarking ‘0’ on the number sleeve 60 is visible through the windows 11 band 114 of the housing 10 and gauge element 110, respectively.

The torsion spring 90, which has a number of pre-wound turns applied toit during assembly of the device, applies a torque to the number sleeve60 and is prevented from rotating by the zero dose abutment 64, 113. Itis also possible to ‘back-wind’ the mechanism slightly due to an offsetbetween the zero dose stop 64, 113 and the angular offset of the drivesleeve 40 spline teeth. This has the effect of preventing possibleweeping when a dose is dialled and the zero dose abutment is disengaged.

The automated assembly of the torsion spring 90 into the number sleeve60 can be achieved by incorporating large lead-ins and a groove featureto the number sleeve 60. As the torsion spring 90 is rotated duringassembly, the hook end form 91 locates in the groove feature beforeengaging the anchor point in the number sleeve 60. To help to preventthe torsion spring 90 disengaging the anchor point during subsequentassembly steps it is possible to create an interference between thetorsion spring 90 and the number sleeve 60, or a one-way clip feature.

The user selects a variable dose of liquid medicament by rotating thedose selector 80 clockwise, which generates an identical rotation in thenumber sleeve 60. Rotation of the number sleeve 60 causes charging ofthe torsion spring 90, increasing the energy stored within it. As thenumber sleeve 60 rotates, the gauge element 110 translates axially dueto its threaded engagement thereby showing the value of the dialleddose. The gauge element 110 has flanges 115, 116 either side of thewindow area 114 which cover the numbers printed on the number sleeve 60adjacent to the dialled dose to ensure only the set dose number is madevisible to the user (see FIGS. 17a and 17b ).

A specific feature of this disclosure is the inclusion of a visualfeedback feature in addition to the discrete dose number display typicalon devices of this type. The distal end, namely flange 115, of the gaugeelement 110 creates a sliding scale through a small window 11 a in thehousing 10 (see FIGS. 17a and 17b ). As an alternative, the slidingscale could be formed using a separate component engaged with the numbersleeve 60 on a different helical track.

As a dose is set by the user, the gauge element 110 translates axially,the distance moved proportional to the magnitude of the dose set. Thisfeature gives clear feedback to the user regarding the approximate sizeof the dose set. The dispense speed of an auto-injector mechanism may behigher than for a manual injector device, so it may not be possible toread the numerical dose display during dispense. The gauge featureprovides feedback to the user during dispense regarding dispenseprogress without the need to read the dose number itself. For example,the gauge display may be formed by an opaque element on the gaugeelement 110 revealing a contrasting coloured component underneath.Alternatively, the revealable element may be printed with coarse dosenumbers or other indices to provide more precise resolution. Inaddition, the gauge display simulates a syringe action during dose setand dispense.

The openings 11 a, 11 b in the housing 10 allow the user to view thegauge feature and number display as shown in FIGS. 17a and 17b . Toreduce dust ingress and prevent the user from touching moving parts,these openings 11 a, 11 b are covered by translucent windows. Thesewindows may be separate components, but in this embodiment they areincorporated into the housing 10 using ‘twin-shot’ moulding technology.A first shot of translucent material forms the internal features and thewindows 11 a, 11 b, and then a ‘second shot’ of opaque material formsthe outer cover of the housing 10.

The mechanism utilises a dose selector 80 with an increased diameterrelative to the housing 10 which aids dialling although this is not arequirement of the mechanism. This feature is particularly useful (butnot essential) for an auto-injector mechanism where a power supply ischarged during dose setting and the torque required to turn the doseselector 80 may be higher than for a non-auto injector device.

The drive sleeve 40 is prevented from rotating as the dose is set andthe number sleeve 60 rotated, due to the engagement of its splined teeth41 with teeth 14 of the housing 10. Relative rotation must thereforeoccur between the clutch plate 120 and drive sleeve 40 via the ratchetinterface 43, 121.

The user torque required to rotate the dose selector 80 is a sum of thetorque required to wind up the torsion spring 90, and the torquerequired to overhaul the ratchet interface 43, 121. The clutch spring130 is designed to provide an axial force to the ratchet interface 43,121 and to bias the clutch plate 120 onto the drive sleeve 40. Thisaxial load acts to maintain the ratchet teeth engagement of the clutchplate 120 and drive sleeve 40. The torque required to overhaul theratchet 43, 121 in the dose set direction is a function of the axialload applied by the clutch spring 130, the clockwise ramp angle of theratchet teeth 43, 121, the friction coefficient between the matingsurfaces and the mean radius of the ratchet interface 43, 121.

As the user rotates the dose selector 80 sufficiently to increment themechanism by one increment, the number sleeve 60 rotates relative to thedrive sleeve 40 by one ratchet tooth. At this point the ratchet teeth43, 121 re-engage into the next detent position. An audible click isgenerated by the ratchet re-engagement, and tactile feedback is given bythe change in torque input required.

Relative rotation of the number sleeve 60 and the drive sleeve 40 isallowed as splines 42, 61 are disengaged during dose setting. Thisrelative rotation also causes the last dose nut 50 to travel along itsthreaded path, towards its last dose abutment at last dose stop 46 onthe drive sleeve 40.

With no user torque applied to the dose selector 80, the number sleeve60 is now prevented from rotating back under the torque applied by thetorsion spring 90, solely by the ratchet interface 43, 121 between theclutch plate 120 and the drive sleeve 40. The torque necessary tooverhaul the ratchet in the anti-clockwise direction is a function ofthe axial load applied by the clutch spring 130, the anti-clockwise rampangle of the ratchet, the friction coefficient between the matingsurfaces and the mean radius of the ratchet features. The torquenecessary to overhaul the ratchet must be greater than the torqueapplied to the number sleeve 60 (and hence clutch plate 120) by thetorsion spring 90. The ratchet ramp angle is therefore increased in theanti-clockwise direction to ensure this is the case whilst ensuring thedial-up torque is as low as possible.

The user may now choose to increase the selected dose by continuing torotate the dose selector 80 in the clockwise direction. The process ofoverhauling the ratchet interface 43, 121 between the number sleeve 60and drive sleeve 40 is repeated for each dose increment. Additionalenergy is stored within the torsion spring 90 for each dose incrementand audible and tactile feedback is provided for each increment dialledby the re-engagement of the ratchet teeth. The torque required to rotatethe dose selector 80 increases as the torque required to wind up thetorsion spring 90 increases. The torque required to overhaul the ratchetin the anti-clockwise direction must therefore be greater than thetorque applied to the number sleeve 60 by the torsion spring 90 when themaximum dose has been reached.

If the user continues to increase the selected dose until the maximumdose limit is reached, the number sleeve 60 engages with its maximumdose abutment 65 on the maximum dose abutment 112 of gauge element 110.This prevents further rotation of the number sleeve 60, clutch plate 120and dose selector 80.

Depending on how many increments have already been delivered by themechanism, during selection of a dose, the last dose nut 50 may contactits last dose abutment 51 with stop face 46 of the drive sleeve 40. Theabutment prevents further relative rotation between the number sleeve 60and the drive sleeve 40, and therefore limits the dose that can beselected. The position of the last dose nut 50 is determined by thetotal number of relative rotations between the number sleeve 60 anddrive sleeve 40, which have occurred each time the user sets a dose.

With the mechanism in a state in which a dose has been selected, theuser is able to deselect any number of increments from this dose.Deselecting a dose is achieved by the user rotating the dose selector 80anti-clockwise. The torque applied to the dose selector 80 by the useris sufficient, when combined with the torque applied by the torsionspring 90, to overhaul the ratchet interface 43, 121 between the clutchplate 120 and drive sleeve 40 in the anti-clockwise direction. When theratchet is overhauled, anti-clockwise rotation occurs in the numbersleeve 60 (via the clutch plate 120), which returns the number sleeve 60towards the zero dose position, and unwinds the torsion spring 90. Therelative rotation between the number sleeve 60 and drive sleeve 40causes the last dose nut 50 to return along its helical path, away fromthe last dose abutment.

With the mechanism in a state in which a dose has been selected, theuser is able to activate the mechanism to commence delivery of a dose.Delivery of a dose is initiated by the user depressing the button 70axially in the distal direction.

When the button 70 is depressed, splines between the button 70 andnumber sleeve 60 are disengaged, rotationally disconnecting the button70 and dose selector 80 from the delivery mechanism, i.e. from numbersleeve 60, gauge element 110 and torsion spring 90. Splines 74 on thebutton 70 engage with splines 15 on the housing 10, preventing rotationof the button 70 (and hence the dose selector 80) during dispense. Asthe button 70 is stationary during dispense, it can be used in thedispense clicker mechanism as shown in FIG. 9. A stop feature in thehousing 10 limits axial travel of the button 70 and reacts any axialabuse loads applied by the user, reducing the risk of damaging internalcomponents.

The clutch plate 120 and drive sleeve 40 travel axially with the button70. This engages the splined tooth interface 42, 61 between the drivesleeve 40 and number sleeve 60 as shown in FIGS. 4b and 7b (splines 42,61 engaged), preventing relative rotation between the drive sleeve 40and number sleeve 60 during dispense (in contrast, in FIGS. 4a and 7asplines 42, 61 are engaged). The splined tooth interface 41, 14 betweenthe drive sleeve 40 and the housing 10 disengages (see FIG. 4b ), so thedrive sleeve 40 can now rotate and is driven by the torsion spring 90via the number sleeve 60, and clutch plate 120.

Rotation of the drive sleeve 40 causes the lead screw 30 to rotate dueto their splined engagement, and the lead screw 30 then advances due toits threaded engagement to the housing 10. The number sleeve 60 rotationalso causes the gauge element 110 to traverse axially back to its zeroposition whereby the zero dose abutment 64, 113 stops the mechanism.

The bearing 140 is axially clipped to the lead screw 30, but free torotate. Since the bearing 140 is in direct contact with the bung 101, itdoes not rotate as the lead screw 30 rotates and advances during dosedispense. As described above, the contact diameter between the bearing140 and lead screw 30 is small to minimise the frictional losses at thisinterface. The design of the lead screw 30 and bearing 140 eliminatesdelicate clip features or large contact diameters present on previousconcepts. This embodiment also allows the lead screw 30 to be assembledaxially, from the proximal end and through the thread engagement to thehousing 10, which simplifies assembly.

Tactile feedback during dose dispense is provided via the compliantcantilever clicker arm 123 integrated into the clutch plate 120. Thisarm 123 interfaces radially with ratchet features 75 on the innersurface of the button 70, whereby the ratchet tooth spacing correspondsto the number sleeve 60 rotation required for a single incrementdispense. During dispense, as the number sleeve 60 rotates and thebutton 70 is rotationally coupled to the housing 10, the ratchetfeatures 75 engage with the clicker arm 123 to produce an audible clickwith each dose increment delivered.

Delivery of a dose continues via the mechanical interactions describedabove while the user continues to depress the button 70. If the userreleases the button 70, the clutch spring 130 returns the drive sleeve40 to its ‘at rest’ position (together with the clutch plate 120 andbutton 70), engaging the splines 14, 41 between the drive sleeve 40 andhousing 10, preventing further rotation and stopping dose delivery.

During delivery of a dose, the drive sleeve 40 and number sleeve 60rotate together, so that no relative motion in the last dose nut 50occurs. The last dose nut 50 therefore travels axially relative to thedrive sleeve 40 during dialling only.

Once the delivery of a dose is stopped, by the number sleeve 60returning to the zero dose abutment, the user may release the button 70,which will re-engage the spline teeth 14, 41 between the drive sleeve 40and housing 10. The mechanism is now returned to the ‘at rest’condition.

It is possible to angle the spline teeth 14, 41 on either the drivesleeve 40 or housing 10 so that when the button 70 is released there-engagement of the spline teeth 14, 41 fractionally ‘backwinds’ thedrive sleeve 40 thereby removing the engagement of the number sleeve 60to the zero dose stop abutment on the gauge element 110. Thiscompensates for the effect of clearances in the mechanism (for exampledue to tolerances) which could otherwise lead to slight advancement ofthe lead screw 30 and medicament dispense when the device is dialled forthe subsequent dose due to the number sleeve 60 zero dose stop notrestraining the mechanism and instead the restraint returning to thesplines between the drive sleeve 40 and housing 10.

At the end of dose dispensing, additional audible feedback is providedin the form of a ‘click’, distinct from the ‘clicks’ provided duringdispense, to inform the user that the device has returned to its zeroposition via the interaction of the clicker arm 67 on the number sleeve60 with the ramp 47 on the drive sleeve 40 and the cam 117 and therecess 118 on the gauge element 110. This embodiment allows feedback toonly be created at the end of dose delivery and not created if thedevice is dialled back to, or away from, the zero position.

FIG. 11a shows the position of the click features when the device is inthe ‘at rest’ condition, with zero units dialled and the button 70 notdepressed. It can be seen that the cam feature 117 on the gauge element110 does not contact the clicker arm 67 on the number sleeve 60 when thebutton 70 is in the ‘at rest’ condition, so during storage or diallingthe clicker arm 67 is not deflected.

During dialling, the gauge element 110 translates in the proximaldirection, so the cam 117 is no longer aligned axially with the clickerarm 67. At the start of dose delivery when the drive sleeve 40translates in the distal direction, the ramp 47 on the drive sleeve 40pushes the clicker arm 67 radially outwards. During dose delivery, thegauge element 110 translates back in the distal direction, and towardsthe end of dose delivery, the clicker arm 67 contacts the cam 117 on thegauge element 110. For small doses, the cam 117 and clicker arm 67 willbe in contact at the start of the dose. FIGS. 11b to 12c show thecomponent interactions. After dose delivery, the button 70 is releasedand the end of dose mechanism returns to its ‘at rest’ position.

In FIG. 11b a dose is dialled and approximately one full dial turn isapplied to number sleeve 60. Gauge element 110 is axially translatedaway from zero unit position, so that cam 117 is no longer alignedaxially with clicker arm 67. FIG. 11c shows the start of dispensing,when button 70 is depressed to initiate dose dispense and which causesthe drive sleeve 70 to translate axially. Ramp 47 on the drive sleeve 40pushes clicker arm 67 radially out and into radial alignment with cam117 on the gauge element 110.

FIG. 12a shows the mechanism at the end of dose dispensing withapproximately 4 units remaining. The gauge element 110 returns axiallytowards its zero unit position, so that cam 117 aligns axially withclicker arm 67. Rotation of number sleeve 60 causes clicker arm 67 tocontact cam 117 such that clicker arm 67 is pushed radially inwards.With approximately 2 units remaining the number sleeve 60 rotatesfurther and clicker arm 67 follows the profile of cam 117 (FIG. 12b ).This radial deflection ‘charges’ clicker arm 67 storing elastic energy.In FIG. 12c dispensing is completed as the number sleeve 60 reaches itszero unit rotational position. The clicker arm 67 drops off the sharpedge of cam 117 into recess 118. Elastic energy is released causingclicker arm 67 to spring radially outwards to contact cam 117 and createa distinct ‘click’.

In the principal embodiment, the lead screw 30 advances by a fixeddisplacement for each revolution of the drive sleeve 40. In otherembodiments, the rate of displacement may vary. For example, the leadscrew 30 may advance a large displacement per revolution to dispense afirst amount of medicament from the cartridge 100 and then a smallerdisplacement per revolution to dispense the rest of the cartridge 100.This is advantageous, as it can compensate for the fact that the firstdose dispensed from the cartridge 100 often has a lower volume thanother doses, for a given displacement of the mechanism.

Using FIGS. 22 to 24 an embodiment communicating to the user that theneedle is blocked is described in more detail with regard to a drugdelivery device comprising above features. It is therefore referred tothe above Figures and explanation as well as reference numbers. The drugdelivery device only differs with regard to the housing which nowcomprises two components, the housing 10 and a body insert 150. The bodyinsert 150 comprises a ring of teeth 151 which corresponds to the ringof teeth 14 of the housing 10 shown in FIGS. 1 to 21. The ring- orsleeve-like body insert 150 is fixedly attached to the housing 10. Theembodiments described below may likewise be realized with a two-parthousing 10, 150 as described and shown in FIGS. 22 to 27 or with aone-part (integral) housing 10 as described in FIGS. 1 to 21.

As indicated above the drug delivery device comprises rotational strainsensing arrangement comprising a locking ring 160 which is axiallyconstrained within the flange like inner wall 12 of the housing 10 butfree to rotate relative to the housing 10. For that the locking ring 160comprises a groove 161 at the outer surface of the locking ring 160. Thegroove 161 cooperates with a radial projection 16 provided at theproximal end of the inner wall 12 (see FIG. 24). The locking ring 160 isaccommodated within the drive sleeve 40 at its distal end. The leadscrew 30 is axially movable within the locking ring 160 by means of asplined connection, the drive sleeve 40 rotates together with thelocking ring 160 during dose dispensing. The locking ring 160 furthercomprises a radial pin 163 projecting from its outer surface andaccommodated within an L-shaped track (e.g. slot) 48 within the drivesleeve 40 at its distal end. The L-shaped track 48 comprises a firstaxial section and a second section (horizontal section) perpendicular tothe longitudinal axis I of the drug delivery device. The L-shaped track48 goes through the drive sleeve 40.

The spline connection between the drive sleeve 40 and the lead screw 30comprising the spline 49 and the groove 35 is located an appreciabledistance from the locking ring 160.

After initiating delivery of a medicament dose by depressing the button70 moving the button 70 from a first extended position to a secondretracted position the drive sleeve 40 is moved distally to disengageits teeth 41 from the body insert 150 clutch teeth 151. This moves thelocking ring 160 locking pin 163 within the L-shaped track 48 along thefirst section so that it is located in the ‘elbow’ of the L-shaped track48. This is shown in FIG. 23.

In the alternative embodiment in which the housing is integrally formedin the retracted position of the button 70 the drive sleeve 40 isdisengaged from the clutch teeth 14 as indicated above.

Once the drive sleeve 40 is released from the body insert 150 or thehousing 10, the dispensing torque of the torsion spring 90 istransferred to the lead screw 30. The lead screw 30 will then deflect ina twisting fashion along the section between the body thread and thedrive sleeve splines, over which the torque is applied. This twistingmotion causes the drive sleeve 40 and with it the L-shaped track 48 torotate until the locking ring 160 locking pin 163 is at the end of thesecond horizontal section (see FIG. 24).

In this state, the drive sleeve 40 is prevented from returning to itsproximal starting position under the action of the clutch spring 130even if the button 70 is released. The components will remain in thisstate until transfer of torque from the torsion (drive) spring 90 isstopped by the engagement of the 0 unit stop features.

So, if the drug delivery device reaches the 0 unit stop, but the needleis blocked and torsion remains in the mechanism, the button 70 willremain in its depressed position providing feedback to the user that theneedle is blocked. If the device does not reach the 0 units as a resultof a blocked needle, the button 70 will also remain in its depressedposition, but the dose display will also not have returned to 0providing additional feedback that the dose has not been completed.

To help the clarity of feedback provided by the button position, a flagor other feature, for example a colored marking (flag) 78 as shown inFIG. 31, for example, may be provided at the outer surface of the button70. If torsion remains in the mechanism, the button 70 keeps itsretracted second position as shown in FIG. 30 and the flag 78 is hiddenby the dose selector 80. The user easily derives the status of thedevice from that. If the flag 78 is visible, the user knows that thedose delivery was finished correctly (see FIG. 31).

In a blocked needle condition, even though the drive sleeve 40 will notactively push the button 70 back to its first extended (proximal)position, if the device is held upside down, it may be possible that thebutton 70 could fall to its second position. To prevent this, a detentfeature may be added between the button 70 and the dose selector 80 thatwas sufficient to resist the weight of the button 70 but not sufficientto resist the force of the clutch spring 130 (applied to the button 70via the drive sleeve 40 and clutch plate 120). With this feature, thebutton 70 would only return to its first position when driven by thedrive sleeve 40 (via the clutch plate 120) in an unblocked needlecondition.

In another embodiment shown in FIG. 25 it may be desirable to allow theuser to interrupt the dispense action of the drug delivery device partway through dispense by removing the distally acting axial force thatthey apply to the button 70.

In this embodiment, if the user removes the force from the button 70,the drive sleeve re-engages the body insert 150 clutch teeth 151 (orteeth 14 of the housing 10), causing it to stop rotating and the drugdelivery device to stop dispensing. In the embodiment explained withregard to FIGS. 22 to 24 above, the drive sleeve 40 is held in thedistal position even if the button 70 is released (by the L-shaped track48). In this distal position, the drive sleeve 40 cannot re-engage thebody insert 150 clutch teeth 151 and dispense is likely to continue.

In contrast, in the embodiment shown in FIG. 25, the second horizontalsection of the L-shaped track 48 is widened (see dashed line 48 a inFIG. 25), i.e. has a higher width into the axial direction of the drugdelivery device, allowing the drive sleeve 40 to move proximally at themoment the pressure to the button 70 is reduced until it starts toengage the body insert 150 clutch teeth 151 and stopping dispense butpreventing it from returning completely to its starting position, sothat the user feedback regarding a blocked needle condition ismaintained.

The principle of operation of another embodiment shown in FIGS. 26 to 27is very similar to that of the embodiment explained with regard to FIGS.22 to 25. The key difference is that the flexibility of the lead screw30, required to achieve relative rotation between the locking ring 160and drive sleeve 40, and causing engagement of the horizontal section ofthe L-shaped track 48, is replaced by flexibility of at least oneflexible arm 49 a on the drive sleeve 40. The arm 49 a extends along thelongitudinal direction I within the plane of the drive sleeve 40 andcomprises a spline feature 49 b that engages the lead screw 30 via theaxial groove 35. The spline feature 49 b extends from the inner surfaceof the flexible arm 49 a and the drive sleeve 40. The flexible arm 49 amay be formed by a cutout within the drive sleeve 40.

As shown in FIG. 27 the flexible arm 49 a is twisted in a tangentialdirection (perpendicular to the longitudinal direction I) caused bytorque of torsion spring 90. Thereby the mechanism is made morereliable. With regard to the operation of this embodiment it is referredto the embodiment explained with regard to FIGS. 22 to 24 wherein thelead screw twisting is replaced by twisting of the flexible arm 49 a.The button 70 cannot return to its first extended position as long asthere is residual torque in the system which twists flexible arm 49 a.

Another embodiment is depicted in FIG. 28. In this embodiment there isno body insert and no L-shaped track within the drive sleeve 40. Incontrast, in this embodiment the torsional load path that exists duringdispense (and remains loaded at the end of the dose if a blocked needleis fitted) passes from the number sleeve lower 60 a to the clutch plate120. When a dose is dispensed, the clutch plate 120 is moved distallyrelative to the number sleeve lower 60 a, but the components remain insplined engagement. In this embodiment, the side of the number sleevespline surface 68 that transfers the torsion to the clutch plate 120 isformed by the number sleeve upper 60 b (which is rigidly connected tothe number sleeve lower 60 a so that together they functionally form asingle component) and has an angled surface.

As long as sufficient torsion is applied between the number sleeve upper60 b and the clutch plate 120 via this number sleeve angled splinesurface 68, the resulting axial load is sufficient to react the axialforce from the clutch spring 130. This causes the clutch plate 120 to beheld in the distal position and thereby prevents the clutch spring 130from returning the button 70 to the first position even if the button 70is released by the user, as long as torsion remains within themechanism. The flag 78 at the button 70 remains hidden by the doseselector 80 showing that there is some problem with the drug deliverydevice and dose dispense was not finished correctly. This buttonretention mechanism alerts the user to the fact that the needle isblocked in the same way as the previously described embodiments. Thebutton 70 is only returned to its first extended position by the clutchspring 130 if the torque in the system is released.

Alternatively, in the fifth embodiment the user is allowed to interruptdose dispensing by removing the force they apply to the button 70. Inthis embodiment, the spline in the number sleeve 60 that transfers thetorque to the clutch plate 120 during dispense is no longer purelyformed as angled surface on the number sleeve upper 60 b only. Instead,it is partially formed by an angled spline surface 68 on the numbersleeve upper 60 b and partially formed by a spline surface 68 b on thenumber sleeve lower 60 a that runs at least parallel to the longitudinalaxis of the drug delivery device. The number sleeve lower 60 a splinesurface 68 b may alternatively be formed with the opposite angle to thenumber sleeve upper 60 b spline surface 68, relative to the longitudinalaxis. Therefore (whether the surface 68 b is parallel to the axis of thedevice or oppositely angled), when the device is dispensing and thisinterface is loaded, if the user releases force from the button 70, theclutch plate 120 is allowed to move proximally until it contacts theangled surface of the number sleeve upper 60 b. This movement issufficient to allow the drive sleeve 40 to engage the body insert 150and stop dispense, but is not sufficient to return the button 70 to itsfully proximal position, i.e. the first position, so that the user wouldstill be made aware that the needle is blocked, for example by viewingthe flag 78.

REFERENCE NUMERALS

10 housing

11 a, b opening

12 flange-like inner wall

13 strip

14 teeth

15 spline

16 radial projection of inner wall

20 cartridge holder

30 lead screw (piston rod)

31 outer thread

32 clip arm

33 concave contact surface

35 longitudinal groove

40 driver (axially movable drive sleeve)

41 teeth

42 spline

43 ratchet teeth

44 threaded section

46 last dose stop

47 ramp

48 L-shaped track

48 a widened L-shaped track

49 spline

49 a flexible arm

49 b spline feature

50 nut (last dose nut)

51 last dose stop

52 spline

60 dose indicator (number sleeve)

60 a number sleeve lower

60 b number sleeve upper

61 spline

62 flange

63 outer thread

64, 65 end stop

66 spline

67 clicker arm

68 angled spline surface of number sleeve upper 60 b

68 b angled spline surface of number sleeve lower 60 a

70 button

71 stem

72 flange

73, 74 spline

75 ratchet teeth

78 flag

80 dose selector

90 torsion spring

91, 92 hook

93, 94 coil

100 cartridge

101 bung

110 gauge element

111 helical feature

112, 113 stop

114 aperture

115, 116 flange

117 cam

118 recess

120 clutch plate

121 ratchet teeth

123 clicker arm

125 clutch plate spline

130 clutch spring

140 bearing

141 disc

142 stem

143 convex contact surface

144 recessed portion

150 body insert

151 teeth

160 locking ring

161 groove

163 radial pin

I longitudinal axis

R direction of revolution

1. A drug delivery device for expelling a pre-determined or pre-settableamount of a liquid medicament formulation, the drug delivery devicecomprising: a medicament reservoir attached to a housing; and anexpelling mechanism configured for acting against the medicamentreservoir in order to expel a portion of the liquid medicamentformulation therefrom, the expelling mechanism comprising: anarrangement of a threaded nut in a fixed axial relation to the housingand a lead screw in threaded engagement with the threaded nut, thethreaded nut and the lead screw being rotatable relative to each otherby a rotational input interface, a mechanical energy reservoir forstoring energy, the energy being releasable from the mechanical energyreservoir by a rotational interface, a drive train having an upstreaminterface coupled to the rotational interface of the mechanical energyreservoir for feeding rotational energy into the drive train and adownstream interface coupled to the rotational input interface of thearrangement of the threaded nut and the lead screw for outputtingrotational energy thereto to thereby rotate the lead screw and thethreaded nut relative to each other, the drive train further beingequipped with a releasable latch for preventing transfer of rotationalenergy from the upstream interface to the downstream interface whenactuated and for allowing transfer of rotational energy from theupstream interface to the downstream interface when released, and atrigger movable relative to the housing from a first position to asecond position, the trigger being connected to the releasable latch foroperating the releasable latch, and the trigger further being biasedtowards the first position opposite to the second position correspondingto release of the releasable latch, wherein the drive train furthercomprises a rotational strain sensing arrangement which is configured toconvert rotational strain into an axial force or an interlocking, theaxial force or the interlocking being applied to the trigger by amechanical linkage to thereby prevent the trigger from returning to thefirst position until the rotational strain acting on the rotationalstrain sensing arrangement of the drive train reduces below apredetermined threshold value.
 2. The drug delivery device according toclaim 1, wherein the mechanical linkage between the trigger and therotational strain sensing arrangement is configured to allow the triggerto leave the second position under any torque strain condition and tomove towards an intermediate position away from the second positionthereby causing re-engagement of the releasable latch.
 3. The drugdelivery device according to claim 1, wherein the releasable latch islocated between the upstream interface and the rotational strain sensingarrangement or wherein the releasable latch is located between thedownstream interface and the rotational strain sensing arrangement. 4.The drug delivery device according to claim 1, wherein the drive trainfurther includes a user-settable end stop limiter configured forenabling a user to restrict an amount of rotation that is transferred bythe drive train upon release of the releasable latch to auser-determined angle.
 5. The drug delivery device according to claim 4,wherein the mechanical energy reservoir is coupled to the user-settableend stop limiter to translate setting of the end stop limiter intoimmediate energizing of the energy reservoir to an extent correspondingto the user-determined angle.
 6. The drug delivery device according toclaim 1, wherein the first position of the trigger is an extendedposition with respect to the housing.
 7. The drug delivery deviceaccording to claim 1, wherein the drive train comprises a drive sleeveand the downstream interface of the drive train comprises a spline atthe drive sleeve, a first splined connection formed by the spline andthe rotational input interface being located at an axial distancerelative to the threaded nut, wherein the rotational strain sensingarrangement includes a locking ring being maintained in a rotationalfixed relation to the lead screw by a second splined connection at aposition located between the first splined connection and the threadednut, the locking ring and the drive sleeve implementing angulardependent axial keying to thereby limit relative axial travel betweenthe locking ring and the drive sleeve when an advancing angle of thedrive sleeve relative to the threaded nut due to torsional deformationexceeds a predefined threshold angle.
 8. The drug delivery deviceaccording to claim 7, wherein the torsional deformation occurs in aflexible arm on the drive sleeve and/or in the lead screw.
 9. The drugdelivery device according to claim 7, wherein the mechanical linkagebetween the trigger and the rotational strain sensing arrangementincludes a mechanical connection that at least partially limits travelof the trigger according to the limitation occurring in an angulardependent axial keying between the drive sleeve and the threaded nut.10. The drug delivery device according to claim 9, wherein the triggeris mechanically connected to an axial movement of the drive sleeveand/or to the threaded nut.
 11. The drug delivery device according toclaim 7, wherein the angular dependent axial keying comprises a slottedengagement of a radial pin rotationally fixed at the locking ring andthe drive sleeve in an L-shaped track to thereby restrict relative axialtravel between the threaded nut and the drive sleeve according arelative angular position thereof.
 12. The drug delivery deviceaccording to claim 11, wherein a second section of the L-shaped trackallows a movement of the radial pin in an axial direction.
 13. The drugdelivery device according to claim 1, wherein the rotational strainsensing arrangement of the drive train comprises a helical interface forconverting the rotational strain into an axial strain.
 14. The drugdelivery device according to claim 13, wherein the mechanical linkagebetween the rotational strain sensing arrangement and the trigger isconfigured to feed an axial force produced by the rotational strainsensing arrangement to the trigger to thereby compensate a biasing forceuntil the rotational strain acting on the rotational strain sensingarrangement of the drive train reduces below the predetermined thresholdvalue.
 15. The drug delivery device according to claim 13, wherein thehelical interface comprises a clutch plate having an outer spline and aproximal section of a number sleeve having an inner spline, wherein atleast one of the outer spline and the inner spline has an angled surfaceor edge, and wherein the clutch plate is axially coupled to the trigger.16. The drug delivery device according to claim 15, wherein the angledsurface or edge of the inner spline comprises a first inner splinesection formed by the proximal section of the number sleeve.
 17. Thedrug delivery device according to claim 16, wherein the angled surfaceor edge of the inner spline further comprises a second inner splinesection formed by a distal section of the number sleeve.
 18. The drugdelivery device according to claim 6, wherein the second position is aretracted position with respect to the housing.
 19. The drug deliverydevice according to claim 1, further comprising the liquid medicamentformulation, the liquid medicament formulation being contained withinthe medicament reservoir.
 20. The drug delivery device according toclaim 1, further comprising the housing to which the medicamentreservoir is attached.